Cardiomyocyte-specific overexpression of Larp6 protects against angiotensin II-induced cardiac dysfunction

Introduction: La ribonucleoprotein 6 (Larp6) is a multifunctional mRNA binding protein that interacts with type I collagen mRNA to increase its half-life, translation, and deposition. However, its role in the heart is not known. To investigate the role of Larp6 in cardiac function and remodeling, we generated a cardiomyocyte-specific Larp6 overexpressing (OE) transgenic mouse model (Larp6-Tg), and investigated its role at (i) baseline and (ii) following hypertensive challenge with angiotensin II (Ang II). We hypothesized that Larp6 OE exacerbates Ang II-induced cardiac remodeling and dysfunction. Methods: Cross-sectional studies were performed from 2-8 months of age in male and female Larp6-Tg and wild-type (WT) littermates. Baseline cardiac function was assessed by 7-T MRI and echocardiography. In another set of mice, hypertension was induced by infusion of Ang II by osmotic minipump (1000 ng/kg/min) and compared to vehicle infusion. Blood pressure (BP) was assessed 14-17 days post-surgery via tail-cuff, cardiac function by echocardiography after 21 days, and a mid-section of heart was fixed for histochemistry. Results: Baseline cross-sectional studies revealed that Larp6 OE had no significant effect on cardiac function (7-T MRI), BP, or gross morphology regardless of sex. At 10 months of age, histochemistry revealed increased cardiomyocyte Larp6 protein expression and fibrosis in Larp6 OE mice. In 10-month-old mice, Ang II infusion increased BP and induced cardiac hypertrophy in both male and female Larp6-Tg and WT mice. Ang II induced systolic dysfunction in WT mice, however Larp6 OE significantly protected against Ang II-induced decreases in ejection fraction, fractional shortening, and cardiac output independent of sex. These data provide insight into novel roles of Larp6 in the heart worth further examination. Conclusions: Transgenic overexpression of Larp6 in cardiomyocytes doesn’t affect basal cardiac function. However, under hypertensive conditions, its overexpression protects against systolic dysfunction independent of sex. These unanticipated protective effects of Larp6 will be further evaluated through histology and transcriptomics to understand the underlying molecular mechanisms of protection. Together, our data show for the first time that induction of Larp6 has potential to blunt the progression of hypertensive heart disease. Funding: NHLBI R01 HL088105, R01 HL136386, R01 HL142770, NIDDK DK130243, SRCS (IK6BX004016), and merit BX005845. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.